Preterm birth results in significant developmental disability, and the incidence of neurodevelopmental handicaps in preterm infants is reported to be unchanged during the past decade. Thus, examination of those factors which may affect developmental outcome is critical. Circulatory disturbances and oxygen deprivation are a major cause of developmental impairments in preterm infants. Although intraventricular hemorrhage is perhaps the most commonly recognized and best studied of these disturbances, hypoxia is particularly prevalent among very low birth weight preterm infants. A developmentally regulated pattern of ingrowth of cortical axonal systems, synaptogenesis, and receptor development is thought to be central to learning and cognition. Although recent data have suggested that the pharmacologic disruption of the genetically programmed onset of synaptogenesis may contribute to cognitive deficits, the effect of hypoxia on the developing brain at different gestational time points are relatively unexplored. These data are of particular importance if one is to both establish an understanding of the mechanisms of injury associated with this insult and provide therapeutic strategies for those who care for these tiny and frequently critically ill subjects. We hypothesize that a dominant factor in the neurodevelopmental handicap resulting from preterm birth is sublethal hypoxic stress. In the previous neonatal exploratory brain research grant funding period, our studies demonstrated that the neonatal rat model of preterm brain responds to chronic sublethal hypoxia with angiogenesis and significant changes in cerebral microvascular permeability. Our preliminary data suggest that this insult alters the profile of developmentally regulated genes in the brain and results in modification of the developmentally regulated pattern of programmed cell death. We hypothesize, therefore, that chronic sublethal hypoxia results in the developmental arrest or delay of many of those cerebral processes critical to learning and cognition, including callosal connectivity, synaptogenesis and programmed cell death.